Heart failure affects 5 million individuals in the U.S. and has a mortality rate of approximately 50%. The underlying basis of the common forms of heart failure, and the factors the lead to its progression are not well understood, and this ultimately affects our abilities to design innovative preventative and treatment strategies. With the advancing decline in function, the failing heart develops a significant diminution in a principal mechanism for increasing cardiac output: activation of the cardiac beta-adrenergic receptor (betaAR) signal transduction system. Whether this serves an entirely protective purpose, or whether certain aspects of this response contribute to the pathophysiology of heart failure is not known. The overall goals of this project are to delineate the contributions of dysfunctional beta1AR and beta2R signalling to the progressive contractile dysfunction in this syndrome, to determine the mechanisms of this alteration at the molecular and genetic levels, and to attempt approaches for rescue of heart failure that further confirm mechanism and may lead to novel therapeutics. These studies will be carried out in transgenic mouse models of hypertrophy and failure and include elements that provide for correlations between biochemical, molecular, and structural abnormalities and physiologic function of the intact heart. The specific areas are: 1) To determine the mechanisms of beta1AR and beta2R regulation in heart failure in transgenic mice engineered to express critical components of the hypertrophy/failure program. 2) To ascertain the relative contributions of the defects in receptor-G protein-effector signalling to the specific characteristics of hypertrophy/failure found in specific aim 1, by experiments aimed at rescuing the transduction pathway via targeted transgenesis. 3) To delineate the relevance of genetic variations (mutations/polymorphisms) of the beta1AR and beta2AR found in the human population to ventricular function within the context of hypertrophy and failure. These studies will be carried out by transgenically expressing these variants in the hearts of mouse models with ventricular dysfunction.